Fractalkine, is a chemokine expressed constitutively by healthy neurons and it has been identified as a novel neuroimmune regulatory protein, whose function is to send alert signals to microglia, and inhibit microglia activity under inflammatory conditions. Disruption of this dialogue could trigger more drastic changes in the functional phenotype of microglia. In contrast to many other chemokines, fractalkine binds to only one receptor (CX3CR1). Evaluation of several pathological processes that did not involve blood brain barrier compromise (and therefore did not entail large scale entry of peripheral leukocytes) showed that signaling through the CX3CR1 receptor reduced neuronal damage. It has also been shown that fractalkine controls the degree of microglia toxicity by attenuating the production of IL-1[unreadable]?and TNFa. The specific hypothesis addressed in this application is that a disruption in the crosstalk between neuronally-derived fractalkine and microglial cell expressed CX3CR1 leads to microglia overactivation by pushing the cytokine profile away from a M2/alternative state towards the M1/classical state, and that IL-1[unreadable]??is one of the key molecules responsible for the deleterious effect of disruption of CX3CR1/fractalkine signaling on cognitive function. Our working hypothesis is supported by our published data in which we show for the first time that there is a decrease in soluble fractalkine protein levels in the aged brain and this may be one of the key players that is disrupted with age, thereby leading to overactivation of the innate immune system. We have further demonstrated that administering fractalkine to aged rats increases proliferation of endogenous neuronal progenitors in the subgranular zone of the dentate gyrus, while blocking the function of CX3CR1 in young rats decreases neuronal progenitor cell proliferation in the subgranular zone. In addition we have new preliminary data showing that CX3CR1-/- mice in non-pathological conditions have reduced synaptic plasticity in the form of decreased neurogenesis and most recently that these mice show reduced LTP and deficits in cognitive function. To the best of our knowledge, there are no data from studies other than ours directly investigating the role of FKN on learning and memory in aged rats. We hypothesize that aging leads to a disruption in CX3CR1/fractalkine signaling, which triggers an increase in IL-1[unreadable] levels. This positive feedback loop leads to neuroinflammation and contributes to impaired cognition. Here, we will test this hypothesis by pursuing the following two specific aims: 1) Microglial dysfunction in CX3CR1-deficient (CX3CR1-/-) mice and increased levels of IL-1[unreadable] lead to functional impairment in cognitive function;2) Impairment in Fractalkine/CX3CR1 signaling modulates hippocampal-dependent age-related memory deficits. Our contribution here is expected to be a detailed understanding of how FKN/CX3CR1 signaling defect in the aged brain leads to a decline in cognitive function.